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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C17/00—Preparation of halogenated hydrocarbons
  • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
  • C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
  • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
  • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
  • C07C233/13—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/90—Carboxylic acid amides having nitrogen atoms of carboxamide groups further acylated
  • C07C233/91—Carboxylic acid amides having nitrogen atoms of carboxamide groups further acylated with carbon atoms of the carboxamide groups bound to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
  • C07C25/24—Halogenated aromatic hydrocarbons with unsaturated side chains
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
  • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
  • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
  • C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
  • C07C33/40—Halogenated unsaturated alcohols
  • C07C33/46—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts
  • C07C33/48—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts with unsaturation outside the aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
  • C07C33/40—Halogenated unsaturated alcohols
  • C07C33/46—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts
  • C07C33/48—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts with unsaturation outside the aromatic rings
  • C07C33/483—Monocyclic
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/62—Halogen-containing esters
  • C07C69/65—Halogen-containing esters of unsaturated acids

Definitions

• the present invention relates to a process for preparing alkali metal salts of diformylamide and to crystalline forms of sodium diformylamide.
• a process for preparing (E)-1-amino-2-(fluoromethylene)4-(p)-fluorophenyl)butane, a compound which is useful as an irreversible inhibitor of monoamine oxidase utilizes alkali metal salts of diformylamide. Generally, these salts are only partially soluble in useful solvents which causes the reaction rate to be surface area dependent.
• the methods for preparing alkali metal salts of diformylamide have the disadvantage that the material is obtained as a solid mass. The solid obtained must be broken up which leads to material of differing and irregular particle size. Moreover, milling alkali metal salts of diformylamide to increase the surface area creates dust and inhalation problems. Further, the method of E. Allenstein and V. Beyl for preparing alkali metal salts of diformylamide, when carried out on large scale, gives material that is contaminated with detrimental amounts of methanol and ammonia.
• An object of the present invetion is to provide a novel process for crystallizing alkali metal salts of diformylamide that gives alkali metal salts of diformylamide as free flowing granular solid that is free of detrimental amounts of methanol and ammonia.
• Another object of the present invention is to provide a novel crystalline form of sodium diformylamide.
• the present invention provides a novel process for crystallising alkali metal salts of diformylamide comprising the steps of:
• the present invention provides for novel a crystalline form of sodium diformylamide characterized by major peaks in the x-ray powder diffraction pattern at values of two theta of 15.60° ⁇ 0.2°, 24.90° ⁇ 0.2°, 27.69° ⁇ 0.2°, 31.23° ⁇ 0.2°, 35.80° ⁇ 0.2°, 37.76° ⁇ 0.2°, 43.10° ⁇ 0.2°, 46.28° ⁇ 0.2°, 51.05° ⁇ 0.2°, and 57.15° ⁇ 0.2° when the x-ray diffraction pattern is measured with a Co K ⁇ 1 x-ray source.
• Alkali metal salts of diformylamide such as lithium diformylamide, sodium diformylamide, and potassium diformylamide are obtained as a granular solid by a novel crystallization process comprising the steps of: dissolving an alkali metal salt of diformylamide in a hydroxylic solvent and removing the hydroxylic solvent by distillation while adding an anti-solvent.
• an alkali metal salt of diformylamide is dissolved in a hydroxylic solvent, such as methanol, ethanol, propanol, isopropanol, butanol, and the like, with methanol being preferred.
• a hydroxylic solvent such as methanol, ethanol, propanol, isopropanol, butanol, and the like.
• the volume of hydroxylic solvent used is not critical but should be kept to a minimal amount as a matter of convenience.
• the solution is heated to the temperature at which the hydroxylic solvent begins to distill and an anti-solvent is added to replace the hydroxylic solvent lost upon distillation.
• an anti-solvent examples include benzene, chlorobenzene, toluene, xylene, cyclohexane, hexane, cyclopentane, heptane, octane, isooctane, dichloromethane, acetonitrile, ethyl acetate, acetone, butanone, tetrahydrofuran and tetrachloroethylene, with benzene, toluene, cyclohexane, tetrahydrofuran and acetonitrile being preferred and toluene being most preferred. Distillation is continued until the alkali metal salt of diformylamide crystallizes. The volume of the solution being decreased as necessary to facilitate crystallization. The distillation may be continued until the hydroxylic solvent is substantially removed. The alkali metal salt of diformylamide is isolated by filtration and dried.
• An alkali metal salt of diformylamide may exist in more than one crystalline form.
• sodium diformylamide may exist in more than one crystalline form.
• a crystalline form of sodium diformylamide, herein designated Form 1 may be identified by an x-ray powder diffraction pattern essentially as shown in Table 1 and another crystalline form of sodium diformylamide, herein designated Form 2, may be identified by an x-ray powder diffraction pattern essentially as shown in Table 2.
• sodium diformylamide can be preparing in substantially pure crystalline form.
• sodium diformylamide may be prepared in substantially pure crystalline form comprising greater than 50% Form 1 sodium diformylamide.
• Form 1 sodium diformylamide is prepared in greater than 70% Form 1 sodium diformylamide.
• Form 1 sodium diformylamide is prepared in greater than 90% Form 1 sodium diformylamide.
• Form 1 sodium diformylamide is prepared in greater than 97% Form 1 sodium diformylamide.
• Starting material for the crystallization described above may be Form 1, Form 2, or any other form of sodium diformylamide or mixtures thereof.
• the desired Form 1 sodium diformylamide may be crystallized using similar conditions for crystallization to those described above.
• sodium diformylamide may be prepared in a hydroxylic solvent from either formamide or diformamide by reaction with sodium metal or sodium alcoholate as is well known in the art.
• Sodium diformylamide prepared in a hydroxylic solvent may be used without isolation in the crystallization process described above.
• X-Ray Powder Diffraction analyses are performed as follows: After grinding the sample in an agate mortar and pestle, the samples were loaded into a quartz (zero scatter) sample holder and covered with a thin polyimide film for the x-ray powder diffraction pattern measurement.
• the x-ray powder diffraction patterns were measured using a powder diffractometer equipped with a Co x-ray tube source, primary beam monochromator, and position sensitive detector. The incident beam was collimated using a 1° divergence slit. The active area on the position sensitive detector subtended approximately 5° two theta.
• the source was operated at 35 kV and 30 mA and the sample was illuminated with Co K ⁇ 1 radiation.
• X-ray powder diffraction data were collected from 5 to 65° two theta at a rate of either 0.25° or 1.25° two theta per minute and a step width of 0.02° two theta.
• the x-ray powder diffraction patterns were measured without the addition of an internal calibrant.
• Peak positions and intensities for the most prominent features were measured using a double-derivative peak picking method. X-ray peaks with I/I O of 10% or greater were reported. The cutoff was chosen arbitrarily. The intensities are rounded to the nearest 5%.
• the error in peak position measurement is estimated to be on the order of 0.2° two theta or less depending on the peak intensity, the peak broadness, the double derivative peak picking method, and the potential sample effects.
• the specific d-space error can be calculated from the diffraction angle using Bragg's law. Certain peaks appear sensitive to preferred orientation that is caused by changes in crystallite morphology. This results in large changes in the I/I O value.

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• Organic Chemistry (AREA)
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• 1995
  • 1995-08-31 US US08/513,501 patent/US5599986A/en not_active Expired - Fee Related
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• 1997
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• 1998
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